Abstract
The receptor-associated prorenin system refers to the pathogenic mechanism whereby prorenin binding to (pro)renin receptor [(P)RR] dually activates the tissue renin-angiotensin system (RAS) and RAS-independent signaling, and its activation contributes to the molecular pathogenesis of various ocular diseases. We recently developed a new single-stranded RNAi agent targeting both human and mouse (P)RR ((P)RR-proline-modified short hairpin RNA [(P)RR-PshRNA]), and confirmed its therapeutic effect on murine models of ocular inflammation. Here, we investigated the efficacy of (P)RR-PshRNA against laser-induced choroidal neovascularization (CNV) and subretinal fibrosis, both of which are involved in the pathogenesis of age-related macular degeneration (AMD). Administration of (P)RR-PshRNA in mice significantly reduced CNV formation, together with the expression of inflammatory molecules, macrophage infiltration, and extracellular signal-regulated kinase (ERK) 1/2 activation. In addition, (P)RR-PshRNA attenuated subretinal fibrosis, together with epithelial-mesenchymal transition (EMT)-related markers including phosphorylated SMAD2. The suppressive effect of (P)RR-PshRNA is comparable with aflibercept, an anti-vascular endothelial growth factor drug widely used for AMD therapy. AMD patient specimens demonstrated (P)RR co-localization with phosphorylated ERK1/2 in neovascular endothelial cells and retinal pigment epithelial cells. These results indicate that (P)RR contributes to the ocular pathogenesis of both inflammation-related angiogenesis and EMT-driven fibrosis, and that (P)RR-PshRNA is a promising therapeutic agent for AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness worldwide.[1]
Anti-vascular endothelial growth factor (VEGF) therapy has become the standard treatment for improving visual acuity; a large percentage of patients suffer from poor visual prognosis because of subretinal fibrosis.[5,6]
We reported that inhibition of angiotensin II type 1 receptor (AT1R) and (P)RR attenuated laser-induced choroidal neovascularization (CNV) and inflammation using the animal model, and demonstrated that receptor-associated prorenin system (RAPS) was involved in CNV formation through activation of its intracellular signaling pathways.[8,9]
Summary
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness worldwide.[1]. Consistent with our previous report in the CNV model,[9] CNV-related elevation of phosphorylated ERK1/2 levels in the RPE-choroid complex was reduced by inhibition of (P) RR with (P)RR-PshRNA at post-laser day 3 (Figures 2N and 2O), suggesting that administration of (P)RR-PshRNA can suppress upregulation of (P)RR/Atp6ap[2], together with both inflammatory molecule expression and CNV formation via ERK1/2 activation.
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